Structurally modified opioids for prevention and treatment of diseases and conditions

Abstract

Aspects of the present invention are directed to structurally modified opioids (SMOs) that result in improved modulating activity at the NMDAR and improved PK and PD parameters over existing drugs with NMDAR modulating activity. The structural modifications of an opioid or opioid enantiomer that result in the SMOs can be obtained by starting the synthetic process de novo; by modifying the synthetic process for the opioid at any intermediate step during the synthesis of the racemate or of one enantiomer; or by modifying the structure of the opioid or opioid enantiomer after the synthesis. The nitric acid ester substitutions are of particular relevance, especially when associated to deuterated substitutions and/or halogen substitutions.

What is claimed is: 
     
         1 . A compound having a structure analogue to dextromethadone according to formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         AR 1  is selected from the group consisting of aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         AR 2  is selected from the group consisting of aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 2  is hydrogen, deuterium or selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 3  is alkyl optionally substituted at one or more positions by deuterium, halogen, hydroxy, alkoxy, nitric acid ester; 
         R 4  is alkyl optionally substituted at one or more positions by deuterium, halogen, hydroxy, alkoxy, nitric acid ester; and 
         n is comprised between 1 and 4. 
       
     
     
         2 . A compound having a structure analogue to levopropoxyphene according to formula II: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         AR 1  is selected from the group consisting of aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         AR 2  is selected from the group consisting of aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 2  is hydrogen, deuterium or selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 3  is alkyl optionally substituted at one or more positions by deuterium, halogen, hydroxy, alkoxy, nitric acid ester; 
         R 4  is alkyl optionally substituted at one or more positions by deuterium, halogen, hydroxy, alkoxy, nitric acid ester; and 
       
       n is comprised between 1 and 4. 
     
     
         3 . A compound having a structure analogue to dextroisomethadone according to formula III: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         AR 1  is selected from the group consisting of aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         AR 2  is selected from the group consisting of aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 2  is hydrogen, deuterium or selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 3  is alkyl optionally substituted at one or more positions by deuterium, halogen, hydroxy, alkoxy, nitric acid ester; 
         R 4  is alkyl optionally substituted at one or more positions by deuterium, halogen, hydroxy, alkoxy, nitric acid ester; and 
         n is comprised between 1 and 4. 
       
     
     
         4 . A compound having a structure analogue to levomoramide according to formula IV: 
       
         
           
           
               
               
           
         
         wherein 
         NR 1 R 2  is optionally cyclized through C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         If NR 1 R 2  is not cyclized R 1  is selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester. R 2  is hydrogen, deuterium or selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         AR 1  is selected from the group consisting of aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         AR 2  is selected from the group consisting of aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 3  is hydrogen; or selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         NR 4 R 5  is optionally cyclized through C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         If NR 1 R 2  is not cyclized R 1  is selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester. R 2  is hydrogen, deuterium or selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; and 
         n is comprised between 1 and 4. 
       
     
     
         5 . A compound having a structure analogue to N-methyl-dextromethadone according to formula V: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         AR 1  is selected from the group consisting of aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         AR 2  is selected from the group consisting of aryl or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 2  is hydrogen, deuterium or selected from the group consisting of alkyl, aryl, C 3 -C 12  cycloalkyl, or heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 3  is alkyl optionally substituted at one or more positions by deuterium, halogen, hydroxy, alkoxy, nitric acid ester; 
         R 4  is alkyl optionally substituted at one or more positions by deuterium, halogen, hydroxy, alkoxy, nitric acid ester; 
         R 5  is alkyl optionally substituted at one or more positions by deuterium, halogen, hydroxy, alkoxy, nitric acid ester; 
         X −  is the nitrogen-counter-ion; and 
         n is comprised between 1 and 4. 
       
     
     
         6 . A compound having a structure analogue to levorphanol according to formula VI: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, deuterium, halogen, hydroxyl, nitro, nitric acid ester or selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 2  is hydrogen, deuterium, halogen, hydroxyl, nitro, nitric acid ester or selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 3  is hydrogen, deuterium, halogen, hydroxyl, nitro, nitric acid ester or selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; and 
         R 4  is hydrogen or selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester. 
       
     
     
         7 . A compound having a structure analogue to dextromethorphan or dextrorphan according to formula VII: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, nitric acid ester or selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 2  is hydrogen, deuterium, halogen, hydroxyl, nitro, nitric acid ester or selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 3  is hydrogen, deuterium, halogen, hydroxyl, nitro, nitric acid ester or selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; 
         R 4  is hydrogen, deuterium, halogen, hydroxyl, nitro, nitric acid ester or selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester; and 
         R 5  is hydrogen or selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, heterocyclyl, any of which are optionally substituted at one or more positions by deuterium, halogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, heterocyclyl, nitro, nitric acid ester.